去势抵抗型前列腺癌雄激素代谢及新生的研究进展

前列腺癌(PCa)经雄激素剥夺治疗(ADT)后普遍进展为去势抵抗型前列腺癌(CRPC),其可能的机制除了AR的扩增、突变及其信号通路的激活外,还与雄激素代谢途径的改变相关。本文综述近年来有关CRPC肿瘤内雄激素含量的改变,及引起这些改变的原因包括雄激素新生、雄激素合成代谢酶活性变化、雄激素合成代谢酶的转运效率的改变以及肿瘤微环境相互作用的改变及其临床应用价值的最新研究进展。     

自噬及其在前列腺癌治疗中的应用

自噬是一种广泛存在于真核细胞内的重要的生理过程。通过分解细胞质等自身成分以维持在营养能量缺乏状态下的细胞代谢平衡以及在代谢应激下清除损伤的细胞器达到细胞存活的目的。近年来,研究发现细胞自噬在前列腺癌的发生、发展、转归中起着重要作用,并为晚期前列腺癌的治疗提供了新颖的思路。本文就细胞自噬及其在前列腺癌治疗中的进展做一综述。     

自噬与前列腺癌

自噬作用被认为具有高度复杂性及环境依赖性,在有些肿瘤中表现为肿瘤抑制和促进相对立两方面影响,比如乳腺癌和前列腺癌。本文综述了自噬对前列腺癌的发生、发展及治疗的最新研究进展。重点突出自噬调节在雄激素剥夺期间的影响,讨论了雄激素对前列腺癌细胞自噬作用所产生的调节效应。通过对一些研究的报道结果进行评价、分析,我们认为:自噬抑制并结合抗雄激素治疗对于前列腺癌是非常有前景的新型治疗方法。     

抑制雄激素代谢和新生:去势抵抗型前列腺癌治疗的新靶点

前列腺癌(PCa)经雄激素剥夺治疗后终将进展为临床难治的去势抵抗型前列腺癌(CRPC),其重要的机制之一就是人体内雄激素代谢途径的改变以及CRPC细胞内雄激素的新生使得PCa能够有效对抗去势后睾丸来源雄激素的大幅度减少。当前,针对雄激素代谢与新生过程中的关键酶开发新一代的靶向抑制剂已成为热点,为更有效地治疗CRPC提供了新的方法和手段。     

雄激素受体相互作用因子在前列腺癌中的表达及其临床意义

目的 探讨雄激素受体(AR)及其相互作用因子在前列腺癌(PCa)中的表达、变异及其对肿瘤预后的影响。方法 基于STRING数据库分析AR及其相互作用因子的相互作用和GO富集;通过UALCAN分析AR及其相互作用因子在PCa中的表达;通过cBioPortal分析AR及其相互作用因子在PCa中表达变异及其与预后的关系。结果 AR及其相互作用因子相互作用网络节点为10,边数为21,平均节点度为4.2,平均局部聚类系数为0.89,其中NCOA2和EP300在AR相互作用网络中节点度最高。UALCAN分析显示RAN、TNK2、PXN和NRIP1在癌组织中上调(P<0.05);相反NCOR1在癌组织中下调(P<0.05);NCOR2、NCOA2、EP300、SOX9和RAN表达水平改变不显著。cBioPortal分析表明近30%的PCa组织中存在AR及其相互作用因子的表达变异,包括基因扩增、基因突变、深度缺失以及多重变异4个类型。AR变异率为18%,主要包括基因扩增和突变;NCOA2变异率为9%,主要变异类型为基因扩增。神经内分泌前列腺癌中的变异类型主要为基因扩增(8.7%),而去势抵...     

前列腺癌双极雄激素治疗的研究进展

双极雄激素治疗(bipolar androgen therapy,BAT)是去势抵抗性前列腺癌(castration resistant pros-tate cancer,CRPC)的新疗法,可显著降低部分患者血清前列腺癌特异性抗原(prostate specific antigen,PSA)水平、提高患者生活质量和恢...     

S期激酶相关蛋白Skp2调控雄激素受体表达及活性在去势抵抗型前列腺癌进展中的作用

目的:检测不同前列腺癌(PCa)细胞系及组织中S期激酶相关蛋白(Skp2)的表达水平,探讨其表达改变对雄激素受体(AR)信号通路及去势抵抗型前列腺癌(CRPC)发生可能的影响。方法:通过Western印迹法检测不同PCa细胞系中Skp2、AR表达;利用RNA干扰技术,转染shRNA敲低CRPC细胞系C4-2或22RV1中Skp2表达,通过Western印迹法检测雄激素处理后细胞中AR、P27表达,通过双荧光素酶报告基因法检测雄激素处理后细胞中雄激素反应元件(ARE)报告基因ARR3-Luc活性;利用免疫组化染色法检测未行内分泌治疗的患者PCa和CRPC组织标本中Skp2、AR表达,分析两者表达差异及相关性。结果:CRPC细胞系C4-2及22RV1较雄激素依赖性细胞系LNCa P中Skp2表达水平显著升高;C4-2细胞中雄激素处理可诱导Skp2表达,而shRNA敲除Skp2不仅可显著上调其下游经典靶分子P27蛋白的表达,还显著降低AR蛋白表达水平。相一致地,C4-2及22RV1细胞系中雄激素处理可增强ARR3-Luc活性,而敲除Skp2可显著抑制雄激素处理前或后的ARR3-Luc活性(P0.05)。此外,CRPC组织较未行内分泌治疗患者PCa组织中Skp2、AR染色显著增强(P0.05),两者表达具有正相关性(r=0.658 1,P0.05)。结论:CRPC中Skp2可增强AR蛋白表达及转录活性,有望成为重要的分子治疗靶点。     

雄激素受体突变在前列腺癌进展中的作用

前列腺肿瘤的生长几乎完全依靠雄激素受体途径,因此对前列腺癌的治疗围绕阻断这条途径为中心来制定。但是这种治疗往往是肿瘤发展到雄激素非依赖阶段最终治疗失败,在这些病例雄激素受体几乎都发生了突变,更多迹象表明肿瘤仍然继续生长发展。这种机制就是雄激素受体突变后仍然保持着其活性功能。雄激素受体突变后促进肿瘤继续发展的分子机制及其治疗策略仍缺乏统一认识,现就此作一综述。     

雄激素抵抗型前列腺癌的新观念与治疗新方案

前列腺癌是世界上最常见的肿瘤之一,每年大约有25万新发病例。随着前列腺特异性抗原（prostate specific antigen,PSA）的出现及其应用的推广,前列腺癌在尚局限于原位、可治愈的早期阶段就可被诊断。当前在美国,约20％的原位前列腺癌患者虽经过有效的局部治疗,病情仍将继续进展、发生远处转移;而约15％的患者一开始就被诊断有远处转移。多数前列腺癌患者在一定时期内对雄激素剥夺（androgen deprivation therapy,ADT）治疗有效,然而最终几乎所有患者都将发展为“雄激素抵抗型前列腺癌”（castrate refractory prostate cancer,CRPC）,对于这些病例,     

去势抵抗性前列腺癌中雄激素生物合成的研究进展

前列腺癌是男性泌尿生殖系统最常见的恶性肿瘤之一。目前去势抵抗性前列腺癌(CRPC)患者中位生存期仅12个月,预后极差,成为了前列腺癌的治疗难题。尽管雄激素剥夺治疗(ADT)去除了循环中绝大多数雄激素,但CRPC仍可通过前列腺癌瘤内自身合成的雄激素或者改变雄激素受体(AR)来适应患者体内低水平雄激素。本文综述了CRPC中T和双氢睾酮(DHT)的主要合成途径及其所涉及的主要酶和不同阶段的患者体内雄激素水平的变化。由于在雄激素合成途径中存在多条通路,阻断单一通路可能导致另一条通路的上调,从而导致雄激素阻断不彻底,进而出现耐药性。因此,明确雄激素的生物合成途径可以为研发靶向阻断关键雄激素合成通路的药物或阻断肿瘤内雄激素生物合成并拮抗雄激素受体的双功能药物提供契机。     

Novel non-AR therapeutic targets in castrate resistant prostate cancer

Castrate resistant prostate cancer (CRPC) remains a disease with significant morbidity and mortality. The recent approval of abiraterone and enzalutamide highlight the improvements which can be made targeting the androgen receptor (AR) axis. Nonetheless, resistance inevitably develops and there is continued interest in targeting alternate pathways which cause disease resistance and progression. Here, we review non-AR targets in CRPC, with an emphasis on novel agents now in development. This includes therapeutics which target the tumour microenvironment, the bone metastatic environment, microtubules, cellular energetics, angiogenesis, the stress response, survival proteins, intracellular signal transduction, DNA damage repair and dendritic cells. Understanding the hallmarks of prostate cancer resistance in CRPC has led to the identification and development of these new targets. We review the molecular rationale, as well at the clinical experience for each of these different classes of agents which are in clinical development.     

Paradigms in androgen/castrate resistant states of prostate cancer in a biomarker era

The last 25 years have witnessed an unprecedented rise in the number of men given a diagnosis of prostate cancer. This has been a major consequence from the clinical application of the biomarker prostate specific antigen (PSA). Importantly, prostate cancer is a malignancy susceptible and adaptative to hormonal changes. Careful understanding of the relation between serum levels of testosterone and PSA is mandatory. Men in whom the prostate has been removed can be considered cured when PSA is no longer detectable and serum testosterone levels are normal. However, this "cured" claim is not possible for those exhibiting castrated levels of testosterone, whether induced or not. The influence of castration in the prognostic paradigm of prostate cancer is transcendental, and serum testosterone levels provide objectivity for proper disease state characterization. Men with metastatic prostate cancer who have not been exposed to hormonal ablation have a different course than men with metastatic lesions resistant to androgen deprivation. These distinctions become complicated when androgen suppression is initiated at earlier states of the disease, or when it is given in response to molecular, not clinical, activity of prostate cancer. Molecular resistance, signaled by rising PSA levels despite castration, in the absence of clinical progression, is a much more common scenario that we must be acquainted with for patient education and proper design of clinical trials.     

Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer

Objectives

Docetaxel is considered first-line chemotherapy for patients with metastatic castrate resistant prostate cancer (CRPC). Carboplatin and paclitaxel have demonstrated activity in CRPC but published data are limited regarding use after docetaxel.

Methods

A retrospective, bi-institutional review was conducted of patients with advanced CRPC treated with carboplatin plus paclitaxel after docetaxel. Therapy was evaluated for tolerability, response, and survival. Endpoints used modified Prostate Cancer Working Group 2 criteria.

Results

Twenty-five patients were identified from February 2000 to March 2008. Median pretreatment PSA was 130.2 ng/ml [range 0.1–2100]. Sites of metastases included bone (88%), lymph nodes (52%), pelvis (32%), lung (28%), and liver (20%). A median 4.5 cycles of docetaxel [range 1–22] were given with a median progression-free survival (PFS) of 12 weeks [range 2–68]. Eighty-eight percent of patients (22/25) were docetaxel-refractory at the initiation of therapy with carboplatin (AUC 4–6) day 1 plus paclitaxel 60–80 mg/m² days 1, 8, and 21 recycled every 28 days. Patients received a median of 3.5 cycles [range 1–8] of carboplatin/paclitaxel with a median PFS of 12 weeks [range 2–35]. Sixty-four percent of patients (16/25) achieved ≥30% reduction in PSA with a median overall survival of 42 weeks [95% CI 30.6–53.5 weeks]. Grade 3 or 4 adverse hematologic events occurred in 11/25 (44%) patients, with no neutropenic fever or grade 3/4 non-hematologic toxicity.

Conclusion

Carboplatin/paclitaxel chemotherapy following docetaxel in metastatic CRPC is well tolerated with favorable PSA response rates and survival. This combination is a viable option after progression on docetaxel-based therapy.     

A two‐drug combination simulation study for metastatic castrate resistant prostate cancer

Background

Prostate cancer often evolves resistance to androgen deprivation therapy leading to a lethal metastatic castrate‐resistant form. Besides androgen independence, subpopulations of the tumor are genetically heterogeneous. With the advent of tumor genome sequencing we asked which has the greater influence on reducing tumor size: genetic background, heterogeneity, or drug potency?

Methods

A previously developed theoretical evolutionary dynamics model of stochastic branching processes is applied to compute the probability of tumor eradication with two targeted drugs. Publicly available data sets were surveyed to parameterize the model.

Results

Our calculations reveal that the greatest influence on successful treatment is the genetic background including the number of mutations overcoming resistance. Another important criteria is the tumor size at which it is still possible to achieve tumor eradication, for example, 2‐4 cm large tumors have at best a 10% probability to be eradicated when 50 mutations can confer resistance to each drug.

Conclusion

Overall, this study finds that genetic background and tumor heterogeneity are more important than drug potency in treating mCRPC. It also points toward identifying metastatic sites early using biochemical assays and/or dPET.

     

Safety and efficacy of sorafenib in patients with castrate resistant prostate cancer: a Phase II study

PurposeWe determined the safety and efficacy of sorafenib in patients with castrate resistant prostate cancer (CRPC).MethodsSixty-four chemotherapy and radiotherapy naïve patients with CRPC received 400 mg sorafenib orally twice daily in 6-week cycles. All patients had bone metastasis, while 16 had lymph node-, 9 had liver-, and 10 had lung metastases. Treatment was continued until disease progression or excessive toxicity.ResultsAll patients were assessable for response. A median of 6.4 consecutive cycles was administered per patient. Median overall survival for all patients was 14.6 months (confidence interval [CI], 8.2–22.2). No complete response (CR) occurred. Of the 35 patients with measurable extraosseous disease, 7 (20%) had a partial response. Overall, 13 patients (20.3%; 95% CI, 4%–32%) achieved a 50% or greater reduction (partial response [PR]) in prostate-specific antigen (PSA) level after two cycles. The median response duration was 2.5 months (95% CI, 1.4 to 4.8), and the median time to progression was 5.9 months (95% CI 3.6 to 7.6). There was no treatment-related death. Toxicities were well tolerated.ConclusionsSorafenib demonstrated some antitumor activity. Further studies are necessary to determine a subgroup of patients who would likely respond better to sorafenib.     

前列腺癌患者去势术后的睾酮水平

目的 探讨进展期前列腺癌患者去势术后平均睾酮水平，以指导内分泌治疗。方法 进展期前列腺癌患者40例，去势术后，未用任何抗雄激素药物，分别于术前、术后1周及1、3、6、9、12个月，观察血清总睾酮和PSA变化。结果 去势术后6个月，40例患者血清睾酮平均水平〈1．9nmol／L（95％可信区间1．2～1．9nmol／L）；13例患者睾酮〉1．9nmol／L，平均Gleason评分为6．8分。术后6个月，36例患者PSA〈1ng／ml，平均Gleason评分为6．3分；4例患者PSA〉1ng／ml，平均Glcason评分为8．0分。结论 前列腺癌患者去势术后，平均血清睾酮水平〈1．9nmol／L，部分患者需继续抗雄激素药物治疗。术后PSA逐渐下降，6个月降至最低值。     

Use of nomograms for predicting survival in patients with castrate prostate cancer

Given the heterogeneity of prognoses in patients with castrate metastatic prostate cancer, the ability to accurately predict survival is vital for optimal patient counseling, selection of treatments, clinical trial design, and interpretation of clinical data. Over the past 20 years, several prognostic models have been developed in an attempt to refine the clinician's predictive ability. Early models were based on patients with more advanced disease. They included variables that are no longer regularly encountered today and involved cumbersome calculations that were not practical for everyday use in the clinic. Recently, 2 point-based nomograms have been developed based on pretreatment variables measured on a routine basis. These models provide a user-friendly format in which to make sophisticated predictions of survival. These models have improved our ability to predict the outcomes of patients with castrate metastatic disease. However, further work to identify novel prognostic markers to improve the accuracy of these predictions is needed.